Cells are the basic building blocks of tissues and organs. Along with the extracellular matrix they produce and maintain they constitute the physical framework of the tissue. In addition, each cell can be regarded as an individual 'computational unit' that contains the entire genetic code of the organism. This interconnected network of individual cells is what ultimately determines the form and function of a tissue or organ, and the study of this network has been recognized as of central importance not only in areas such as embryology but also in other biological processes that exhibit a strong spatial component to their etiology such as cancer. A central challenge for biologists in the post genomic world is to develop techniques that show how this genetic blueprint is deployed in the 3D environment of a tissue or organ. Ideally in meeting this challenge imaging techniques that can image intact organs and tissue with sufficient detail to reveal the 3D morphology and underlying genetic state of individual cells will be developed that can help bridge the divide between the genotype and phenotype of an organ on both a microscopic and macroscopic scale. This proposal describes the development of a high throughput Two-Photon Tissue Cytometer that is capable if imaging entire mouse organs with subcellular detail in less than a few hours. It has multi-spectral capabilities, integrated microtomy, and high sensitivity detectors particularly well suited for deep tissue imaging. We will apply this system to the study of the metastasis by tracking the metastatic cascade of solitary cancer cells throughout an entire organ. We believe this class of instrument will have wide applicability to a wide host of problems in tissue physiology.